Alstonine (1) and serpentine (2) are pentacyclic alkaloids proposed to contain a zwitterionic indolo[2,3-a]quino-lizidine, referred to as an anhydronium base (FIG. 1A). This structural motif is rare among natural products and is especially unusual in total synthesis, with the only examples being strychnoxanthine (3) and melinonine-E (4). Alstonine has recently been identified as the major component of a plant-based treatment used in Nigeria by traditional healers to treat psychotic disorders. However, the scarcity and lack of purity from natural sources, as well as the uncertainty regarding its exact mechanism of action, illustrates the need for an asymmetric synthesis to enable further study. The related trans diastereomer, serpentine, exhibits anticancer and antimalarial properties and there have been limited efforts at elucidating its mechanism of action.
The closely related heteroyohimbine family of alkaloids (FIG. 1B) has elicited the interest of numerous synthetic groups for multiple decades, with representative alkaloids of this family including tetrahydroalstonine (5), akuammigine (6), and ajmalicine (7). These natural products are structurally similar to alstonine and serpentine, only differing in ring saturation and relative stereochemistry at C3 and C20 (FIG. 1B). Though 80 years have passed since the first isolations of alstonine (from Alstonia constricta) and serpentine (from Rauvolfia serpentina), surprisingly, no total syntheses of these specific compounds have been reported to date. Accordingly, there remains an on-going search in the art for enantioselective syntheses of these and other such indole alkaloids and their natural product progenitors (e.g., 5 and 6).